tbuckley/cabot-search huggingface dataset:
Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models
Authors: Liangping Su, Yitian Chen, Cheng Huang, Sangqing Wu, XiaoJuan Wang, Xinbao Zhao, Qiuping Xu, Ruipu Sun, Xiangzhan Kong, Xue Jiang, Xiaoyi Qiu, Xiaoming Huang, Minghui Wang, Ping-Pui Wong
Journal: Science Translational Medicine (2023)

Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src-signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.
Age at Diagnosis of Type 2 Diabetes and Depressive Symptoms, Diabetes-Specific Distress, and Self-Compassion
Authors: Mary M. Barker, Melanie J. Davies, Francesco Zaccardi, Emer M. Brady, Andrew P. Hall, Joseph J. Henson, Kamlesh Khunti, Amelia Lake, Emma L. Redman, Alex V. Rowlands, Jane Speight, Tom Yates, Jack A. Sargeant, Michelle Hadjiconstantinou
Journal: Diabetes Care (2023)

OBJECTIVE To investigate the association between age at diagnosis of type 2 diabetes and depressive symptoms, diabetes-specific distress, and self-compassion among adults with type 2 diabetes. RESEARCH DESIGN AND METHODS This analysis used data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycemic Control (CODEC) cross-sectional study. Information was collected on depressive symptoms, diabetes-specific distress, and self-compassion, measured using validated self-report questionnaires, in addition to sociodemographic and clinical data. Multivariable regression models, adjusted for diabetes duration, sex, ethnicity, deprivation status, prescription of antidepressants (selective serotonin reuptake inhibitors), and BMI were used to investigate the association between age at diagnosis of type 2 diabetes and each of the three psychological outcomes. RESULTS A total of 706 participants were included; 64 (9.1%) were diagnosed with type 2 diabetes at &amp;lt;40 years, 422 (59.8%) between 40 and 59 years, and 220 (31.2%) at ≥60 years of age. After adjustment for key confounders, including diabetes duration, younger age at diagnosis was significantly associated with higher levels of depressive symptoms (βadj: −0.18 [95% CI −0.25 to −0.10]; P &amp;lt; 0.01) and diabetes-specific distress (βadj: −0.03 [95% CI −0.04 to −0.02]; P &amp;lt; 0.01) and lower levels of self-compassion (βadj: 0.01 [95% CI 0.00 to 0.02]; P &amp;lt; 0.01). CONCLUSIONS Diagnosis of type 2 diabetes at a younger age is associated with lower psychological well-being, suggesting the need for clinical vigilance and the availability of age-appropriate psychosocial support.
First-Line Catheter Ablation for Paroxysmal Atrial Fibrillation — Have We Reached the Tipping Point?
Authors: Roopinder K. Sandhu, Christine M. Albert
Journal: New England Journal of Medicine (2023)

Atrial fibrillation is a heterogeneous disorder with a variable course. Approximately one third of cases of atrial fibrillation that start out as short, self-terminating paroxysmal episodes progress to longer-lasting persistent attacks over time.1,2 Once the transition from paroxysmal to persistent atrial fibrillation occurs, the likelihood of treatment success decreases and the risks of adverse clinical outcomes increase.3,4 Therefore, treatment strategies to prevent progression to persistent forms of atrial fibrillation are needed. However, what strategies are successful and how early do we need to intervene? Randomized trials have consistently shown that a treatment strategy that includes ablation results in lower rates . . .
The Safety of Inpatient Health Care
Authors: David W. Bates, David M. Levine, Hojjat Salmasian, Ania Syrowatka, David M. Shahian, Stuart Lipsitz, Jonathan P. Zebrowski, Laura C. Myers, Merranda S. Logan, Christopher G. Roy, Christine Iannaccone, Michelle L. Frits, Lynn A. Volk, Sevan Dulgarian, Mary G. Amato, Heba H. Edrees, Luke Sato, Patricia Folcarelli, Jonathan S. Einbinder, Mark E. Reynolds, Elizabeth Mort
Journal: New England Journal of Medicine (2023)

Adverse events during hospitalization are a major cause of patient harm, as documented in the 1991 Harvard Medical Practice Study. Patient safety has changed substantially in the decades since that study was conducted, and a more current assessment of harm during hospitalization is warranted.
Reverse mentoring—never stop learning
Authors: SA Raju, DS Sanders
Journal: BMJ (2023)

You finish your morning rounds, a little later than hoped, and as you leave you overhear a fed-up junior doctor questioning your plans and time management.What do you do?This is not just a situations judgement test (SJT) question, something juniors will know all about, but a real situation.The healthcare workforce currently consists of up to five generations and is becoming more diverse as it includes under-represented groups. 1 We should focus, therefore, on opening communication and finding solidarity across generations, as best practice, technology, and attitudes change over time.The Multisource Feedback, also known as a 360
7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection
Authors: Ulrika Marking, Oscar Bladh, Sebastian Havervall, Julia Svensson, Nina Greilert-Norin, Katherina Aguilera, Martha Kihlgren, Ann-Cristin Salomonsson, Maja Månsson, Radiosa Gallini, Cecilia Kriegholm, Philip Bacchus, Sophia Hober, Max Gordon, Kim Blom, Anna Smed-Sörensen, Mikael Åberg, Jonas Klingström, Charlotte Thålin
Journal: The Lancet Infectious Diseases (2023)
Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters
Authors: Ai-Ris Y Collier, Jessica Miller, Nicole P Hachmann, Katherine McMahan, Jinyan Liu, Esther A Bondzie, Lydia Gallup, Marjorie Rowe, Eleanor Schonberg, Siline Thai, Julia Barrett, Erica N Borducchi, Emily Bouffard, Catherine Jacob-Dolan, Camille R Mazurek, Audrey Mutoni, Olivia Powers, Michaela Sciacca, Nehalee Surve, Haley VanWyk, Cindy Wu, Dan H Barouch
Journal: New England Journal of Medicine (2023)

Immunogenicity of BA.5 Bivalent mRNA Vaccine BoostersTo the Editor: Waning immunity after messenger RNA (mRNA) vaccination and the emergence of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have led to reduced mRNA vaccine efficacy against symptomatic infection and severe disease. 1,2Bivalent mRNA boosters (manufactured by Pfizer-BioNTech and Moderna) expressing the spike protein of the B.1.1.529(omicron) BA.5 sublineage and the ancestral WA1/2020 strain have been developed because BA.5 substantially evades neutralizing antibodies. 3However, the immunogenicity of the BA.5-containing bivalent mRNA boosters remains unknown.We evaluated immune responses in 15 participants who had received the original monovalent mRNA boosters and in 18 participants who had received the bivalent mRNA boosters of the two vaccines (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).The participants received a median of three doses of vaccine against SARS-CoV-2, and 33% had documentation of SARS-CoV-2 infection during the omicron surge, although it is likely that the majority of the participants had hybrid immunity before boosting, given the high incidence of BA.5 infection during the summer and fall of 2022.Both the monovalent and bivalent mRNA boosters led to preferential expansion of WA1/2020 neutralizing antibody titers and lower BA.5 neutralizing antibody titers (Fig. 1A and 1B and Fig. S1).The median BA.5 neutralizing antibody titer increased from 184 to 2829 after monovalent mRNA boosting and from 211 to 3693 after bivalent mRNA boosting.Binding antibody responses were similar after monovalent and bivalent mRNA boosting by enzyme-linked immunosorbent and electrochemiluminescence assays (Fig. S2 andS3).
Case 1-2023: A 49-Year-Old Man with Hypokalemia and Paranoia
Authors: Chad W. Vokoun, Mark C. Murphy, Kerry L. Reynolds, Melanie S. Haines
Journal: New England Journal of Medicine (2023)

A 49-year-old man was admitted with hypokalemia and paranoia. Small-cell lung cancer had been diagnosed 6 months earlier; he had declined medical therapy and pursued alternative treatment. A diagnostic test was performed.
In Vitro Properties and Pharmacokinetics of Temporarily PEGylated Onc72 Prodrugs
Authors: Gubran Khalil Mohammed, Roland Böttger, Andor Krizsan, Daniela Volke, Marina Mötzing, Shyh‐Dar Li, Daniel Knappe, Ralf Hoffmann
Journal: Advanced Healthcare Materials (2023)

The favorable properties of antimicrobial peptides (AMPs) to rapidly kill pathogens are often limited by unfavorable pharmacokinetics due to fast degradation and renal clearance rates. Here, a prodrug strategy linking proline-rich AMP Onc72 to polyethylene glycol (PEGs) with average molecular weights of 5 and 20 kDa via a peptide linker containing a protease cleavage site is tested for the first time in vivo. Onc72 is released from these 5k- and 20k-prodrugs in mouse serum with half-life times (t
Activated regulatory T-cells promote duodenal bacterial translocation into necrotic areas in severe acute pancreatitis
Authors: Juliane Glaubitz, Anika Wilden, Fabian Frost, Sabine Ameling, Georg Homuth, Hala Mazloum, Malte Christoph Rühlemann, Corinna Bang, Ali A Aghdassi, Christoph Budde, Tilmann Pickartz, Andre Franke, Barbara M Bröker, Uwe Voelker, Julia Mayerle, Markus M Lerch, Frank-Ulrich Weiss, Matthias Sendler
Journal: Gut (2023)

In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Treg activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.The prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+ IELs. Treg depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa Escherichia/Shigella which associates with severe disease and infected necrosis was diminished in Treg depleted animals.Tregs play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregs in AP may help to ameliorate the disease course.
Sport and exercise medicine/physiotherapy publishing has a gender/sex equity problem: we need action now!
Authors: Sallie M Cowan, Joanne L Kemp, Clare L Ardern, Jane S Thornton, Ebonie Kendra Rio, Andrea M Bruder, Andrea Britt Mosler, Brooke Patterson, Melissa Haberfield, Eliza A Roughead, Harvi Hart, Laura To, Sydney Neufeld, Nada Mazahir, Kay M Crossley
Journal: British Journal of Sports Medicine (2023)

Objectives We aimed to determine (1) the proportion of women authors overall, in first (lead) and last (senior) author positions, (2) the proportion of women research participants and (3) the association between women in first and/or last author positions and the proportion of women research participants in original research articles and editorials/opinion pieces in four sport and exercise medicine/physiotherapy journals. Methods The journals evaluated were the British Journal of Sports Medicine , Journal of Orthopaedic and Sports Physical Therapy , Physical Therapy in Sport and International Journal of Sports Physical Therapy . We reviewed all original research articles and editorials/opinion pieces published in 2008, 2009, 2018 and 2019. For each, we aimed to determine the gender/sex of all authors (through gender pronouns, Google Scholar, ResearchGate, institutional profiles, personal websites, photographs and/or social media), and the gender/sex of study participants reported as ‘female’ or ‘male’ or ‘women’ or ‘men’ or ‘girls’ or ‘boys’. Results We included 952 original studies and 219 editorials/opinion pieces. There were 5146 authors of original studies and 706 authors of editorials/opinion pieces. Compared with 2008/2009, the proportion of women as first and last authors was 3.6% (33.0% compared with 29.4%) and 4.8% (33.2% compared with 27.4%) higher respectively in 2018/2019. On average, the proportion of women participants in original studies remained largely unchanged over the 10-year period, only 10% of all participants were women in studies. Conclusion Women are strikingly under-represented in first and last author positions, as are women participants in sports and exercise medicine/physiotherapy journals.
Preclinical mouse model of a misfolded PNLIP variant develops chronic pancreatitis
Authors: Guoying Zhu, Steven J Wilhelm, Leah G George, Brett M Cassidy, Sammy Zino, Cliff J Luke, Mina Hanna, Stephen Stone, Nhung Phan, Neel Matiwala, Samuel J Ballentine, Mark E Lowe, Xunjun Xiao
Journal: Gut (2023)

Objective Increasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism. Design We created a mouse model of Pnlip p.T221M and characterised the structural and biochemical changes in the pancreas aged 1–12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR. Results We demonstrated the hallmarks of human CP in Pnlip p.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. The Pnlip p.T221M pancreas had increased ER stress evidenced by dilated ER, increased Hspa5 (BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation of Ddit3 (CHOP), nuclear factor-κB and cell death. Conclusion Expression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.
S100A10 promotes HCC development and progression via transfer in extracellular vesicles and regulating their protein cargos
Authors: Xia Wang, Hongyang Huang, Karen Man-Fong Sze, Jin Wang, Lu Tian, Jingyi Lu, Yu-Man Tsui, Hoi Tang Ma, Eva Lee, Ao Chen, Joyce Lee, Ying Wang, Judy Wai Ping Yam, Tan-To Cheung, Xinyuan Guan, Irene Oi-Lin Ng
Journal: Gut (2023)

Growing evidence indicates that tumour cells exhibit characteristics similar to their lineage progenitor cells. We found that S100 calcium binding protein A10 (S100A10) exhibited an expression pattern similar to that of liver progenitor genes. However, the role of S100A10 in hepatocellular carcinoma (HCC) progression is unclear. Furthermore, extracellular vesicles (EVs) are critical mediators of tumourigenesis and metastasis, but the extracellular functions of S100A10, particularly those related to EVs (EV-S100A10), are unknown.The functions and mechanisms of S100A10 and EV-S100A10 in HCC progression were investigated in vitro and in vivo. Neutralising antibody (NA) to S100A10 was used to evaluate the significance of EV-S100A10.Functionally, S100A10 promoted HCC initiation, self-renewal, chemoresistance and metastasis in vitro and in vivo. Of significance, we found that S100A10 was secreted by HCC cells into EVs both in vitro and in the plasma of patients with HCC. S100A10-enriched EVs enhanced the stemness and metastatic ability of HCC cells, upregulated epidermal growth factor receptor (EGFR), AKT and ERK signalling, and promoted epithelial-mesenchymal transition. EV-S100A10 also functioned as a chemoattractant in HCC cell motility. Of significance, S100A10 governed the protein cargos in EVs and mediated the binding of MMP2, fibronectin and EGF to EV membranes through physical binding with integrin αⅤ. Importantly, blockage of EV-S100A10 with S100A10-NA significantly abrogated these enhancing effects.Altogether, our results uncovered that S100A10 promotes HCC progression significantly via its transfer in EVs and regulating the protein cargoes of EVs. EV-S100A10 may be a potential therapeutic target and biomarker for HCC progression.
Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles
Authors: Shenghua Gao, Letian Song, Yusen Cheng, Fabao Zhao, Dongwei Kang, Shu Song, Mianling Yang, Bing Ye, Wei Zhao, Yajie Tang, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Journal: Acta Pharmaceutica Sinica B (2023)

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
Extracellular vesicle-encapsulated CC16 as novel nanotherapeutics for treatment of acute lung injury
Authors: Yohan Han, Yin Zhu, Sultan Almuntashiri, Xiaoyun Wang, Payaningal R. Somanath, Caroline A. Owen, Duo Zhang
Journal: Molecular Therapy (2023)

Acute lung injury (ALI) is still associated with high mortality. Growing evidence suggests that Club Cell Protein 16 (CC16) plays a protective role against ALI. However, the doses of recombinant CC16 (rCC16) used in preclinical studies are supraphysiological for clinical applications. Extracellular vesicles (EVs) are nanovesicles endogenously generated by mammalian cells. Our study demonstrated that CC16 is released via small EVs and EV-encapsulated CC16 (sEV-CC16) and has anti-inflammatory activities, which protect mice from lipopolysaccharide (LPS) or bacteria-induced ALI. Additionally, sEV-CC16 can activate the DNA damage repair signaling pathways. Consistent with this activity, we observed more severe DNA damage in lungs from Cc16 knockout (KO) than wild-type (WT) mice. Mechanistically, we elucidated that CC16 suppresses nuclear factor κB (NF-κB) signaling activation by binding to heat shock protein 60 (HSP60). We concluded that sEV-CC16 could be a potential therapeutic agent for ALI by inhibiting the inflammatory and DNA damage responses by reducing NF-κB signaling.
Individualized Approach to Management of Light Chain Amyloidosis
Authors: Giovanni Palladini, Paolo Milani
Journal: Journal of the National Comprehensive Cancer Network (2023)

Systemic light chain (AL) amyloidosis is caused by a B-cell (most commonly plasma cell) clone that produces a toxic light chain that forms amyloid fibrils in tissues and causes severe, progressive organ dysfunction. The clinical presentation is protean, and patients are usually extremely frail, thus requiring careful adaptation of the treatment approach. However, the severity of organ involvement can be accurately assessed with biomarkers that allow a sharp prognostic stratification and precise tailoring of the treatment strategy. Moreover, the availability of biomarker-based response criteria also allows adjustment of the treatment approach over time. The recent completion of 3 large randomized clinical trials has offered new evidence for designing appropriate treatments. All this information has recently been integrated in the joint guidelines of the International Society of Amyloidosis and the European Hematology Association for the treatment of AL amyloidosis. Other clinical trials are underway testing new agents directed against the amyloid clone and the amyloid deposits. Our understanding of the peculiarities of the amyloid clone, as well as our ability to detect residual clonal disease and improve organ dysfunction, are also being refined and will result in more precise personalization of the treatment approach.